Stabilized liquid formulation of levothyroxine

ABSTRACT

The present invention relates to stabilized liquid formulations of Levothyroxine or a pharmaceutically acceptable salt thereof, intended for parenteral administration. Further this invention also describes process of preparing such compositions.

BACKGROUND OF THE INVENTION

Thyroxine active drugs are known for both therapeutic and prophylactictreatment of thyroid disorders. The thyroid accomplishes its regulationfunctions by producing the hormones L-triiodothyronine (liothyronine;T3) and L-thyroxine (levothyroxine; T4). The physiological actions ofthyroid hormones are produced predominantly by T3, the majority of which(approximately 80%) is derived from T4 by deiodination in peripheraltissues.

Administration of levothyroxine sodium provides T4 to a patient. Onceabsorbed, the administered T4 behaves identically to T4 that otherwisewould be secreted by the thyroid gland of the patient, and binds to thesame serum proteins, providing a supply of circulating T4-thyroglobulinin the patient. The administered T4 may be deiodinated in vivo to T3. Asa result, a patient receiving appropriate doses of levothyroxine sodiumwill exhibit normal blood levels of T3, even when the patient's thyroidgland has been removed or is not functioning.

Levothyroxine sodium is prescribed for thyroid hormone replacementtherapy in cases of reduced or absent thyroid function e.g., ailmentssuch as myxedema, cretinism and obesity. Levothyroxine sodium is quiteunstable, hygroscopic and degrades rapidly when subjected to highhumidity, light or high temperature. Because of the physicochemicalproperties of the drug, formulations of levothyroxine sodium haveextremely short stability duration, worsened under conditions of highhumidity and temperature.

Levothyroxine sodium is available in the form of capsules, tablets andparenteral dosage forms. Levothyroxine sodium for injection is availableas sterile lyophilized product for parenteral administration containing100 mcg/vial, 200 mcg/vial and 500 mcg/vial.

Conventional formulations of levothyroxine sodium for injection arepreservative-free lyophilized powders containing synthetic crystallinelevothyroxine sodium, mannitol, tribasic sodium phosphate, and sodiumhydroxide. These conventional formulations typically contain 10 mgmannitol, 700 μg of tribasic sodium phosphate and 100 mcg or 200 mcg or500 mcg of levothyroxine sodium. Administration of the conventionalformulation involves reconstitution of the lyophilized powder in 5 mL of0.9% sodium chloride injection, to provide injectable solutions havinglevothyroxine sodium concentrations of 20 mcg/mL, 40 mcg/mL or 100mcg/mL.

U.S. Pat. No. 9,006,289, issued on Apr. 14, 2015, to Jiang, et al.,discloses lyophilized composition comprising of levothyroxine sodium, aphosphate buffer and mannitol.

Levothyroxine has extremely short stability, worsened under conditionsof high humidity and temperature. Due to this instability, Levothyroxineinjectable formulations are used in the form of lyophilized formulationsthat are dissolved in 0.9% sodium chloride Injection immediately beforeinjection. The present inventors have developed stable liquidformulations of Levothyroxine intended for parenteral administration.

SUMMARY OF THE INVENTION

One object of the invention provides stable liquid parenteralpharmaceutical formulation of Levothyroxine.

Another aspect of the invention provides stable liquid parenteralpharmaceutical formulation of Levothyroxine comprising Levothyroxine,buffering agents, one or more solvents and other pharmaceuticallyacceptable excipients thereof.

Yet another aspect of the invention provides liquid parenteralpharmaceutical formulation of Levothyroxine comprising Levothyroxinesodium, buffering agents, stabilizing agents, one or more solvents andother pharmaceutically acceptable excipients thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to stable liquid parenteral formulation ofLevothyroxine, and more particularly to stable Levothyroxine liquidformulation comprising of buffering agents, stabilizing agents, solventsand other pharmaceutically acceptable excipients thereof.

In the context of this invention “Levothyroxine” refers to thepharmaceutically acceptable salts, solvates, hydrates and anhydrousforms thereof. The formulations of the present invention preferablycomprise Levothyroxine sodium.

As used herein, “liquid parenteral formulations of Levothyroxine” refersto formulations that contain Levothyroxine in dissolved or solubilisedform and are intended to be used as such or upon dilution in intravenousdiluents.

Levothyroxine sodium is quite unstable, hygroscopic and degrades rapidlywhen subjected to high humidity, light or high temperature. Degradationis further enhanced by the presence of water. Hence, attempts to developan intravenous preparation of Levothyroxine were limited.

The inventors of the present invention have surprisingly found that itis possible to develop stable liquid parenteral pharmaceuticalformulation of Levothyroxine, despite its rapid degrading nature.

One embodiment of the invention relates to liquid parenteralpharmaceutical formulations of Levothyroxine comprising:

-   -   i. Levothyroxine    -   ii. buffering agents    -   iii. one or more solvents and        other pharmaceutically acceptable excipients thereof.

Yet another embodiment of the invention relates to liquid parenteralpharmaceutical formulation of Levothyroxine comprising:

-   -   i. Levothyroxine sodium    -   ii. buffering agents,    -   iii. stabilizing agents and/or solubilizing agents    -   iv. one or more solvents and    -   v. optionally one or more pharmaceutically acceptable excipients        selected from pH adjusting agents and anti-oxidants.

Stabilizing agents used in the formulation include, but not limited tosodium iodide, potassium iodide and the like. The pharmaceuticalcompositions of the present invention may also contain solubilizingagents such as cyclodextrins. These agents may be used in theformulation to maintain the solubility and stability of levothyroxinesodium during the entire shelf life of the formulation. Suitablecyclodextrins include but not limited to α, β and γ-cyclodextrin andcyclodextrins modified with alkyl-, hydroxyalkyl-, dialkyl-, andsulfoalkyl-ether modified cyclodextrins such as methyl or hydroxypropylβ-cyclodextrins (HPβCD), methyl-and-ethyl-β-cyclodextrin,sulfoalkylether-substituted beta-cyclodextrin,sulfobutylether-β-cyclodextrin (SBECD) and the like.

Suitable buffering agents include amino acids such as arginine, alanine,histidine, glycine and lysine; citrate, glutamate, bicarbonate,tartrate, benzoate, lactate, gluconate, TRIS, acetate, meglumine, borateand phosphate buffer.

Suitable solvents include, but not limited to dimethylacetamide,dimethyl sulfoxide, N-methylpyrrolidone, dimethylisosorbide, ethanol,propylene glycol, polyethylene alcohol, propylene glycol esters,polyethylene glycols, glycerine, water and the like. Preferred solventsare water and propylene glycol.

Suitable pH adjusting agents include sodium hydroxide, sodium carbonate,sodium bicarbonate, potassium hydroxide, ammonium carbonate,hydrochloric acid, citric acid, lactic acid, phosphoric acid, sodiumphosphate, sulfuric acid and the like.

The pharmaceutical compositions of the present invention may alsocontain one or more anti-oxidants such as sodium sulfite, sodiumbisulfite, sodium metabisulfite, sodium thio sulphate, sodiumformaldehyde sulfoxylate, citric acid, tocopherol, butylated hydroxyanisole, butylated hydroxy toluene, monothioglycerol, ascorbic acid,sodium ascorbate and propyl gallate.

The inventors carried out experiments with various buffering agents todetermine suitable buffering agent in the final formulation.Levothyroxine formulations prepared were tested for stability at 60±2°C. (3 days). The data is summarized in table 1.

TABLE 1 Evaluation of different buffering agents for their suitabilityin the formulation. Quantity in mg Ingredients A1 A2 A3 A4 A5 A6Levothyroxine sodium 0.05 0.05 0.05 0.05 0.05 0.5 Arginine 10 — — — — —Sodium carbonate buffer — 10 — — — — Sodium hydrogen — — 10 — — —carbonate buffer — — — — — — Tris buffer — — — 8 — — Tri basic sodiumphosphate — — — — 2.3 — dodeca hydrate buffer — — — — — — Megluminebuffer — — — — — 1 Mannitol 1.5 1.5 1.5 1.5 1.5 — Sodium hydroxide q.sto adjust the pH 11.0 ± 1.0 Water for Injection Qs to 1 ml Observations60 ± 2° C. (3 days) Total impurities 3.14 5.49 6.42 5.82 11.99 4.8

A preferred embodiment of the invention relates to liquid parenteralpharmaceutical formulation of Levothyroxine comprising:

-   -   i. Levothyroxine sodium    -   ii. stabilizing agents and/or solubilizing agents selected from        sodium iodide, potassium iodide and cyclodextrins    -   iii. buffering agent(s) selected from aminoacids such as        arginine, alanine, histidine, glycine and lysine; citrate,        glutamate, bicarbonate, tartrate, benzoate, lactate, gluconate,        TRIS, acetate, borate and phosphate buffer    -   iv. one or more solvents selected from the group comprising        water, polyethylene glycol, ethanol, propylene glycol and        glycerine    -   v. optionally one or more pharmaceutically acceptable excipients        selected from pH adjusting agents and anti-oxidants.

Levothyroxine formulation prepared according to the invention was testedfor stability at 2-8° C., 25° C. and 60° C. for a period of 1 month. Thestability data of the invention formulation is summarized in table 2.

TABLE 2 Stability data of the product prepared according to example 5Levothyroxine sodium Invention formulation stability data Storagecondition 2-8° C. 2-8° C. 25° C. 25° C. 60° C. 60° C. Storage duration 1week 1 month 1 week 1 month 1 week 1 month Total impurities 0.39 0.500.43 0.55 0.58 1.10 pH 6.25 6.40 6.67 6.81 6.21 6.47 Osmolality 272 255263 238 266 262 (mOsm/kg)

Surprisingly no significant increase in impurities was observed even ataccelerated conditions. The data confirms the inventors' finding thatLevothyroxine formulations in the presence of suitable excipientsresulted in a stable product.

The following examples further describe certain specific aspects andembodiments of the present invention and demonstrate the practice andadvantages thereof. It is to be understood that the examples are givenby way of illustration only and are not intended to limit the scope ofthe invention in any manner.

Example 1

Ingredients Quantity Levothyroxine sodium 0.01-1 mg Arginine 0.01-4 mgPropylene glycol 0.01-1 ml Sodium hydroxide qs Water for injection Qs to0.1-2 ml

Manufacturing Process

Water for injection was taken in a compounding vessel and arginine wasadded and stirred. Propylene glycol was added to the above solution andstirred. Then the bulk solution was cooled to 2° C. to 8° C.Levothyroxine sodium was added and stirred till a clear solution wasobtained, while maintaining the temperature at 5±3° C. pH of thesolution was adjusted to 11±1.0 by the addition of sodium hydroxidesolution. The solution was filtered, followed by stoppering and sealingof the vials.

Example 2

Ingredients Quantity Levothyroxine sodium  0.01-1 mg Alanine 0.006-4 mgPropylene glycol  0.01-1 ml Sodium hydroxide qs Water for injection Qsto 0.1-2 ml

Manufacturing Process

Water for injection was taken in a compounding vessel and alanine wasadded and stirred. Propylene glycol was added to the above solution andstirred. Then the bulk solution was cooled to 2° C. to 8° C.Levothyroxine sodium was added and stirred till a clear solution wasobtained, while maintaining the temperature at 5±3° C. The solution wasfiltered, followed by stoppering and sealing of the vials.

Example 3

Ingredients Quantity Levothyroxine sodium 0.01-1 mg L-Arginine  250 mcgSodium acetate anhydrous 10500 mcg Potassium hydroxide  1500 mcg Sodiummetabisulfite  500 mcg Sodium iodide  1000 mcg Water for injection Qs to0.1-6 ml

Manufacturing Process

L-Arginine was added to the manufacturing vessel containing water forinjection, sodium acetate anhydrous was added to the above solution andstirred well. Potassium hydroxide was added to the above solutionfollowed by the addition of sodium metabisulfite and sodium iodide. Thesolution was cooled to 2-8° C. Levothyroxine sodium was added to theabove solution and stirred till a homogeneous solution was obtained.

Example 4

Ingredients Quantity Levothyroxine sodium 0.01-1 mg Arginine  250 mcgSodium acetate anhydrous 10500 mcg Potassium hydroxide  1500 mcg Sodiumiodide  1000 mcg Water for injection Qs to 0.1-6 ml

Manufacturing Process

Arginine was added to the manufacturing vessel containing water forinjection, sodium acetate anhydrous was added to the above solution andstirred well. Potassium hydroxide was added to the above solutionfollowed by the addition of sodium iodide.

The solution was cooled to 2-8° C. Levothyroxine sodium was added to theabove solution and stirred till a homogeneous solution was obtained.

Example 5

Ingredients Quantity Levothyroxine sodium 0.01-1 mg Arginine 0.05 mgSulfobutylether-β-cyclodextrin (SBECD) 83.9 mg Sodium iodide 2.00 mgWater for injection Qs to 0.1-3 ml

Brief Manufacturing Process

SBECD was added to the manufacturing vessel containing water forinjection followed by the addition of Levothyroxine sodium. Arginine wasadded and stirred well, till a clear solution was obtained. Sodiumiodide was added to the above solution. The pH of the solution wasadjusted to 6.0±1.0 (if necessary) with sodium hydroxide/hydrochloricacid.

1-6. (canceled)
 7. A stable liquid parenteral pharmaceutical formulationof Levothyroxine comprising: (i) levothyroxine sodium in a concentrationof less than 0.1% w/v; (ii) one or more excipients selected from thegroup comprising stabilizing agents and solubilising agents; (iii) oneor more buffering agents; (iv) one or more solvents, and optionally (iv)one or more pharmaceutically acceptable excipients, wherein the contentof total impurities is less than 2% w/w, when stored at 60° C. for 1week.
 8. The formulation of claim 1, wherein the content of totalimpurities is less than 2% w/w, when stored at 60° C. for 1 month. 9.The formulation of claim 1, wherein buffering agent is selected from thegroup comprising arginine, alanine, histidine, glycine and lysine,citrate, glutamate, bicarbonate, tartrate, benzoate, lactate, gluconate,TRIS, acetate, meglumine, borate and phosphate buffer.
 10. Theformulation of claim 1, wherein the solubilising agent comprises acyclodextrin.
 11. The formulation of claim 4, wherein the cyclodextrinis selected from α, β and γ-cyclodextrin and cyclodextrins modified withalkyl-, hydroxyalkyl-, dialkyl-, and sulfoalkyl-ether modifiedcyclodextrins.
 12. The formulation of claim 1, wherein one or moresolvents are selected from the group comprising water, polyethyleneglycol, ethanol, propylene glycol and glycerine.
 13. A stable liquidparenteral pharmaceutical formulation of Levothyroxine comprising: (i)levothyroxine sodium in a concentration of less than 0.1% w/v; (ii) oneor more excipients selected from the group comprising stabilizing agentsand solubilising agents; (iii) one or more buffering agents selectedfrom the group comprising arginine, alanine, histidine, glycine andlysine, citrate, glutamate, bicarbonate, tartrate, benzoate, lactate,gluconate, TRIS, acetate, meglumine, borate and phosphate buffer; (iv)one or more solvents selected from the group comprising water,polyethylene glycol, ethanol, propylene glycol and glycerine, andoptionally (iv) one or more pharmaceutically acceptable excipients,wherein the content of total impurities is less than 2% w/w, when storedat 60° C. for 1 week.